Download Irbesartan/Hydrochlorothiazide

Direction de l’Evaluation
des Médicaments et des Produits Biologiques
PUBLIC ASSESSMENT REPORT
Scientific Discussion
COBERSIGAL / COABESART / COTENAHYP
150 mg/12.5 mg, 300 mg/12.5 mg and 300 mg/25 mg
Film-coated tablets
(Irbesartan/Hydrochlorothiazide)
FR/H/452FR/H/452-454/01454/01-03/DC
Applicant: MEDIPHA SANTE SN
Date of the PAR: June 2011
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Information about the initial procedure:
Application/Legal Basis
Active substance
Pharmaceutical form
Strength
Applicant
EU-Procedure number
End of procedure
1.
Generic 10 (1)
Irbesartan/Hydrochlorothiazide
Film-coated tablet
150 mg/12.5 mg, 300 mg/12.5 mg and 300
mg/25 mg
MEDIPHA SANTE SN
FR/H/452-454/01-03/DC
26.01.2011
INTRODUCTION
Based on review of the quality, safety and efficacy data, the decentralised procedure for
COBERSIGAL / COABESART / COTENAHYP 150 mg/12.5 mg, 300 mg/12.5 mg and 300
mg/25 mg film-coated tablet was approved on January, 26th, 2011 for the following indication:
Treatment of essential hypertension.
A comprehensive description of the indications and doses is given in the SmPC.
This decentralised procedure application concerns generic medicinal products of Co-Aprovel 150
mg/12.5 mg, 300 mg/12.5 mg and 300 mg/25 mg registered by Sanofi-Aventis since 1998 through a
centralised procedure. The concerned member states are Estonia, Hungary, Lithuania, Latvia, Poland,
Slovenia, Slovakia, Italy, Germany, Denmark, Finland, Norway and Sweden.
No new preclinical or clinical studies were conducted, which is acceptable for this kind of application.
One bioequivalence study is submitted to show the bioequivalence between IrbesartanHydrochlorothiazide 300/25 mg and the reference product.
During the procedure, a potential serious risk to public health concerns was raised regarding the
commercial batch but this issue was resolved by adequate responses of the applicant at D190.
The procedure was ended positively on 28th January 2011.
2.
QUALITY ASPECTS
2.1 Introduction
Irbesartan/hydrochlorothiazide tablets are presented as oblong, biconvex film-coated tablets. Strengths
150/12.5mg and 300/12.5mg are plain and light pink; strength 300/25mg is red-brick and has a scoreline. The quantitative formulations of the 150/12.5 mg tablets and 300/25 mg tablets are dose weight
proportional. The quantitative formulations of the 300/12.5 mg tablets and 300/25 mg tablets are
similar. The product is packed in white PVC/PE/PVDC/Aluminium blisters.
2.2 Drug substances
Irbesartan
The drug substance Irbesartan is described in the Ph. Eur. The active substance manufacturer has
submitted full details of manufacture into the Active Substance Master File.
Irbesartan is a white to almost white crystalline powder insoluble in water. Irbesartan shows
polymorphism phenomenon, form A is produced by the active substance manufacturer.
The specifications adopted by the drug product manufacturer are those of the Ph. Eur. monograph
completed by additional tests. According to data provided, a retest period of 24 months has been
granted.
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Hydrochlorothiazide
The drug substance hydrochlorothiazide is described in the Ph. Eur. and the manufacturer holds a CoS
of the monograph (Certificate No. R1-CEP2004-307-Rev00).
Hydrochlorothiazide is a white or almost white crystalline powder very slightly soluble in water.
The drug product manufacturer‘s specifications correspond to the requirements of the monograph of
the Ph. Eur. with additional tests.
According to the CEP, the retest period is of 5 years.
2.3 Medicinal product
The pharmaceutical development of irbesartan/hydrochlorothiazide tablets had to take into account the
instability of hydrochlorothiazide when in contact with water, the important contribution of irbesartan
in the formulation which has poor compressibility characteristics and the poor solubility of the two
drug substances. Adequate dissolution studies of the proposed formula have been performed. The
discriminatory character of the dissolution method has been demonstrated.
Discrete batch sizes have been specified for each tablet strength. The manufacturing process consists
of a wet granulation, compression and film coating. The process validation as performed is of good
quality.
All the excipients used in the manufacture of the irbesartan/hydrochlorothiazide film-coated tablets,
except the film-coating agents, are controlled according to the requirements of the corresponding Ph.
Eur. monographs. The coating agents are made of components complying with the quality standards of
the Ph. Eur or with the specifications of the Directive 95/45/EC relating to specific purity criteria
concerning colours for use in foodstuffs. The coating agents are tested according to an in-house
monograph.
The drug product specifications cover appropriate parameters for this dosage form. It has been
confirmed that the 300/25 mg tablet is not to be considered as breakable.
The conditions used in the stability studies comply with ICH stability guideline. Based on the
submitted results up to 9 months and the supported statistical analysis the proposed shelf-life of 18
months with the storage conditions “Do not store above 30°C” and “Store in the original package in
order to protect from light” is approvable”.
3.
NON-CLINICAL ASPECTS
3.1 Discussion on the non-clinical aspects
Pharmacodynamic, pharmacokinetic and toxicological properties of irbesartan-hydrochlorothiazide are
well known. The applicant has not provided additional studies and no further studies are required as
irbesartan and hydrochlorothiazide are well-known active substances. Overview based on literature
review is appropriate.
The non-clinical data are clearly reflected in section 5.3 of the SmPC and in line with Co-Aprovel
product information.
Environmental risk assessment
Environmental risk assessment is not required. This product is intended to substitute for other identical
products on the market. The approval of this product does not result in an increase of the total quantity
of irbesartan and hydrochlorothiazide released into the environment. It does not contain any
component which results in additional hazard to the environment during storage, distribution, use and
disposal.
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4.
CLINICAL ASPECTS
4.1 Introduction
As all clinical data concerning irbesartan and hydrochlorothiazide have already been evaluated, this
application consists essentially in the demonstration of the bioequivalence between irbesartan hydrochlorothiazide generic and the innovator.
Irbesartan and hydrochlorothiazide are well-known active substances with established efficacy and
tolerability.
4.2 Discussion on the clinical aspects
Irbesartan and Hydrochlorothiazide is a combination of an angiotensin-II receptor antagonist,
irbesartan and a thiazide diuretic, hydrochlorothiazide. The combination of these ingredients has an
additive antihypertensive effect, reducing blood pressure to a greater degree than either component
alone.
Irbesartan is a potent, orally active, selective angiotensin-II receptor (AT1 subtype) antagonist. It is
expected to block all actions of angiotensin-II mediated by the AT1 receptor, regardless of the source
or route of synthesis of angiotensin-II. The selective antagonism of the angiotensin-II (AT1) receptors
results in increases in plasma rennin levels and angiotensin-II levels, and a decrease in plasma
aldosterone concentration.
Hydrochlorothiazide is a thiazide diuretic. The mechanism of antihypertensive effect of thiazide
diuretics is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption,
directly increasing excretion of sodium and chloride in approximately equivalent amounts. The
diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity,
increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonate loss,
and decreases in serum potassium.
Pharmacovigilance System
As described, the PV System adequately covers all the requested information, including: i) the
qualified person responsible for pharmacovigilance (including the backup procedure to apply in the
absence of the EUQP), ii) the documented procedures; iii) databases; iv) training and v) the
documentation (including the locations of the different types of pharmacovigilance source documents,
and archiving arrangements).
Risk Management Plan
In view of the existing knowledge and experience with the active substances irbesartan and
hydrochlorothiazide, the available data and the known risk benefit profile, a specific RMP is not
justified. Routine Pharmacovigilance with adequate Pharmacovigilance System as described and
completed by the applicant are sufficient to adequately follow up the safety profile of irbesartan and
hydrochlorothiazide.
4.3 Pharmacokinetics
Pharmacokinetic studies Number 14710/08-09
In support of the present application, a bioequivalence study comparing the PK profile of the
irbesartan-hydrochlorothiazide 300/25 mg formulation to the reference formulation Co-Aprovel in
healthy volunteers under fasting conditions has been conducted.
This study was designed according to a single-dose, randomised, 2-way crossover in fasting conditions
scheme. The treatment phases were separated by a washout period of 7 days.
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Plasma concentrations of irbesartan-hydrochlorothiazide were monitored over 72 hours time period
after drug administration and samples were assayed by the means of a validated HPLC/MS/MS
method.
A total of 48 healthy were enrolled in the study and randomised; only 45 subjects completed the study
and were included in the pharmacokinetic and statistical evaluation.
The primary pharmacokinetic parameters of irbesartan-hydrochlorothiazide assessed were AUC0-t,
AUC0-inf, Cmax and Tmax.
The statistical analysis of the data was conducted according to up to date methods. The analysis
consisted in an ANOVA and estimation of 90% Confidence intervals of the ratios T/R for each PK
parameter of interest
The main results of the bioequivalence study are tabulated below.
Irbesartan: Pharmacokinetic parameters (non-transformed values; arithmetic mean ± SD, tmax
median, range) n=45
Treatment
AUC0-t
AUC0-∞**
Cmax
Tmax
ng.h/ml
ng.h/ml
ng/ml
h
Test
CV
18178.222
(6842.7221)
19396.471
(7025.6958)
3493.726
(1257.8279)
1.50 (0.50,
5.00)
Reference
CV
17838.516
(6237.1714)
19502.139
(6691.0935)
3166.085
(1075.7944)
1.75 (0.75,
5.00)
101.99
99.73
111.16
(95.88 (93.80-106.04)
(103.90108.49)
118.92)
17.56%
17.44%
19.21%
Intra-subject CV
AUC0-t area under the plasma concentration-time curve from time zero
AUC0-∞ area under the plasma concentration-time curve from time zero
Cmax maximum plasma concentration
tmax
time for maximum plasma concentration mediane
*ln-transformed values
*Ratio (90% CI)
Hydrochlorothiazide Pharmacokinetic parameters (non-transformed values; arithmetic mean ±
SD, tmax median, range) n=45
Treatment
AUC0-t
AUC0-∞**
Cmax
Tmax
ng.h/ml
ng.h/ml
ng/ml
h
Test
CV
1261.596
(367.2678)
1294.935
(373.7088)
165.606
(53.5246)
2.00 (1.25,
5.00)
Reference
CV
1216.081
(314.9757)
1251.550
(326.8185)
162.968
(54.1156)
2.25 (1.00,
5.00)
103.47
103.29
102.42
(97.6 – 109.65) (97.69-109.20) (93.93-111.67)
16.46%
15.81%
24.77%
Intra-subject CV
AUC0-t area under the plasma concentration-time curve from time zero
AUC0-∞ area under the plasma concentration-time curve from time zero
Cmax maximum plasma concentration
tmax
time for maximum plasma concentration median
*Ratio (90% CI)
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Based on the submitted bioequivalence study Irbesartan + hydrochlorothiazide 300/25 mg tablets
could be considered bioequivalent with COAPROVEL 300/25 mg tablets.
The bioequivalence study could be extrapolated to the other strengths as all criteria for biowaiver are
fulfilled according to the Note for Guidance on the Investigation of Bioavailability and
Bioequivalence CPMP/EWP/QWP/1401/98, section 5.4.
5.
OVERALL DISCUSSION , BENEFIT/RISK ASSESSMENT AND
RECOMMENDATION
Satisfactory chemical-pharmaceutical documentation has been provided, assuring consistent and
sufficient quality of the product.
Considering the extensive knowledge on the preclinical and clinical data for irbesartan and
hydrochlorothiazide, and given human experience, it can be stated that the irbesartanhydrochlorothiazide tablets do not raise any new pre-clinical or clinical concerns.
Based on the submitted bioequivalence studies, the irbesartan-hydrochlorothiazide tablets are
considered bioequivalent with the reference product.
In conclusion, the Concerned Member States mutually recognised the French evaluation of the
marketing authorisation; all issues being solved for the marketing authorisation of COBERSIGAL /
COABESART / COTENAHYP 150 mg/12.5 mg, 300 mg/12.5 mg and 300 mg/25 mg film-coated
tablet.
There was no discussion in the CMDh.
The current SmPC, Package Leaflet (PL) and labelling are in the agreed template.
User consultation
The package leaflet has been evaluated via a user consultation study in accordance with the
requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The results show that the package
leaflet meets the criteria for readability as set out in the Guideline on the readability of the label and
package leaflet of medicinal products for human use. Twenty-one respondents were recruited for the 2
rounds of interviews.
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